934 research outputs found
Targeting CD83 in mantle cell lymphoma with anti-human CD83 antibody
Objectives: Effective antibody–drug conjugates (ADCs) provide potent targeted cancer therapies. CD83 is expressed on activated immune cells including B cells and is a therapeutic target for Hodgkin lymphoma. Our objective was to determine CD83 expression on non-Hodgkin lymphoma (NHL) and its therapeutic potential to treat mantle cell lymphoma (MCL) which is currently an incurable NHL. Methods: We analysed CD83 expression on MCL cell lines and the lymph node/bone marrow biopsies of MCL patients. We tested the killing effect of CD83 ADC in vitro and in an in vivo xenograft MCL mouse model. Results: CD83 is expressed on MCL, and its upregulation is correlated with the nuclear factor κB (NF-κB) activation. CD83 ADC kills MCL in vitro and in vivo. Doxorubicin and cyclophosphamide (CP), which are included in the current treatment regimen for MCL, enhance the NF-κB activity and increase CD83 expression on MCL cell lines. The combination of CD83 ADC with doxorubicin and CP has synergistic killing effect of MCL. Conclusion: This study provides evidence that a novel immunotherapeutic agent CD83 ADC, in combination with chemotherapy, has the potential to enhance the efficacy of current treatments for MCL
Ballistic matter waves with angular momentum: Exact solutions and applications
An alternative description of quantum scattering processes rests on
inhomogeneous terms amended to the Schroedinger equation. We detail the
structure of sources that give rise to multipole scattering waves of definite
angular momentum, and introduce pointlike multipole sources as their limiting
case. Partial wave theory is recovered for freely propagating particles. We
obtain novel results for ballistic scattering in an external uniform force
field, where we provide analytical solutions for both the scattering waves and
the integrated particle flux. Our theory directly applies to p-wave
photodetachment in an electric field. Furthermore, illustrating the effects of
extended sources, we predict some properties of vortex-bearing atom laser beams
outcoupled from a rotating Bose-Einstein condensate under the influence of
gravity.Comment: 42 pages, 8 figures, extended version including photodetachment and
semiclassical theor
Improving BDD Based Symbolic Model Checking with Isomorphism Exploiting Transition Relations
Symbolic model checking by using BDDs has greatly improved the applicability
of model checking. Nevertheless, BDD based symbolic model checking can still be
very memory and time consuming. One main reason is the complex transition
relation of systems. Sometimes, it is even not possible to generate the
transition relation, due to its exhaustive memory requirements. To diminish
this problem, the use of partitioned transition relations has been proposed.
However, there are still systems which can not be verified at all. Furthermore,
if the granularity of the partitions is too fine, the time required for
verification may increase. In this paper we target the symbolic verification of
asynchronous concurrent systems. For such systems we present an approach which
uses similarities in the transition relation to get further memory reductions
and runtime improvements. By applying our approach, even the verification of
systems with an previously intractable transition relation becomes feasible.Comment: In Proceedings GandALF 2011, arXiv:1106.081
Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state
Lower limb biomechanics during running in individuals with Achilles tendinopathy: a systematic review
<p>Abstract</p> <p>Background</p> <p>Abnormal lower limb biomechanics is speculated to be a risk factor for Achilles tendinopathy. This study systematically reviewed the existing literature to identify, critique and summarise lower limb biomechanical factors associated with Achilles tendinopathy.</p> <p>Methods</p> <p>We searched electronic bibliographic databases (Medline, EMBASE, Current contents, CINAHL and SPORTDiscus) in November 2010. All prospective cohort and case-control studies that evaluated biomechanical factors (temporospatial parameters, lower limb kinematics, dynamic plantar pressures, kinetics [ground reaction forces and joint moments] and muscle activity) associated with mid-portion Achilles tendinopathy were included. Quality of included studies was evaluated using the Quality Index. The magnitude of differences (effect sizes) between cases and controls was calculated using Cohen's d (with 95% CIs).</p> <p>Results</p> <p>Nine studies were identified; two were prospective and the remaining seven case-control study designs. The quality of 9 identified studies was varied, with Quality Index scores ranging from 4 to 15 out of 17. All studies analysed running biomechanics. Cases displayed increased eversion range of motion of the rearfoot (d = 0.92 and 0.67 in two studies), reduced maximum lower leg abduction (d = -1.16), reduced ankle joint dorsiflexion velocity (d = -0.62) and reduced knee flexion during gait (d = -0.90). Cases also demonstrated a number of differences in dynamic plantar pressures (primarily the distribution of the centre of force), ground reaction forces (large effects for timing variables) and also showed reduced peak tibial external rotation moment (d = -1.29). Cases also displayed differences in the timing and amplitude of a number of lower limb muscles but many differences were equivocal.</p> <p>Conclusions</p> <p>There are differences in lower limb biomechanics between those with and without Achilles tendinopathy that may have implications for the prevention and management of the condition. However, the findings need to be interpreted with caution due to the limited quality of a number of the included studies. Future well-designed prospective studies are required to confirm these findings.</p
Making sense of a new technology in clinical practice: a qualitative study of patient and physician perspectives
Explaining Gender-Specific Racial Differences in Obesity Using Biased Self-Reports of Food Intake
Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord
Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord
Assessment of contractility in intact ventricular cardiomyocytes using the dimensionless ‘Frank–Starling Gain’ index
This paper briefly recapitulates the Frank–Starling law of the heart, reviews approaches to establishing diastolic and systolic force–length behaviour in intact isolated cardiomyocytes, and introduces a dimensionless index called ‘Frank–Starling Gain’, calculated as the ratio of slopes of end-systolic and end-diastolic force–length relations. The benefits and limitations of this index are illustrated on the example of regional differences in Guinea pig intact ventricular cardiomyocyte mechanics. Potential applicability of the Frank–Starling Gain for the comparison of cell contractility changes upon stretch will be discussed in the context of intra- and inter-individual variability of cardiomyocyte properties
Acute sleep deprivation has no lasting effects on the human antibody titer response following a novel influenza A H1N1 virus vaccination
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